DNA rearrangements have been found to occur near cellular oncogene loci in tumor cells, activating the oncogenes and inducing a deregulation in cellular growth control. The major goal of this project will be to understand the chromosomal translocation that occurs at the c-myc locus in mouse plasmacytomas, linking the oncogene to the immunoglobulin locus. The Ig gene region will be tested for the presence of transcriptional enhancing sequences. The c-myc intron sequences that function as a bidirectional promoter after translocation will also be studied for enhancing activity and for their ability to substitute for an essential, transcription factor binding domain in the SV40 promoter. Finally, the chromatin structure surrounding the translocated c-myc gene will be analyzed for nuclease sensitivity and the presence of hypersensitive sites. In a related study, the c-myc gene has been used to detect and clone novel mouse cellular sequences that promise to be members of a family of myc-related cellular genes. The mouse genes will be cloned and sequenced to determine their relationship to the previously identified c- and N-myc oncogenes. These genes will be studied for their regulation in development and in the cell cycle, and used to screen for DNA rearrangements in human tumors. Finally, a series of fibroblast clones that have been selected for spontaneous anchorage-independent growth will be studied for the presence of oncogene DNA rearrangements. The frequency at which these variants arise and their relatively stable phenotype suggest that they have suffered a heritable genetic change. Particular emphasis will be placed on detecting gene amplification, a frequent mechanism by which myc oncogenes are activated. Each of these studies is designed to understand cellular oncogenes and the molecular mechanisms by which they are activated in cancer cells.